Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 11, Issue 2, 2011

Stroke, either ischemic or hemorrhagic, is the leading cause of adult disability and the second leading cause of death worldwide. According to The World Stroke Organization, one in six people alive today will at some time have a stroke, and every six seconds someone somewhere will die from a stroke. Therefore, the fight against stroke has been put at the top of the global health agenda, and having up-to-date information is crucial. In this thematic issue devoted to the hot topic “Recent Advances in Stroke: Molecular Mechanisms, Approaches, and Treatments,” the expert authors provide a state-of-the-art update on a variety of aspects of stroke including relevant approaches, treatments, biological models, and molecular mechanisms. In addition, a discussion is provided of clinical trials of potential central nervous system agents as well as current usage of imaging techniques including magnetic resonance imaging and computed tomography. First, Dr. Wang and coworkers give an update on central nervous system neuroprotective agents, focusing on those that counteract apoptosis, inflammation, and oxidation, as well as glutamate inhibitors. They report on studies of ischemic stroke in experimental animals in vivo, organotypic/acute brain slices ex vivo, and cell cultures in vitro. Dr. Jordan et al. present interesting insights into mitochondrial participation in ischemic neuronal death and discuss the potential benefit of the mitochondrial modulator agent minocycline in ischemic stroke. With the aim of bringing attention to the possibility of targeting toll-like receptors for stroke drug development, Drs. Hara and Hamanaka discuss the recent reports concerning the association of Toll-like receptors with cerebral ischemia. Ras family small GTPases are activated following ischemic stroke to become critical regulators; thus they are also potential therapeutic targets in supporting neuronal recovery. Dr. Shi and colleagues explore the contribution of Ras family GTPases to neuroprotective signaling cascades in ischemic stroke. Histone deacetylases are not only promising targets for therapeutic intervention in ischemic stroke, but may also play important roles in hemorrhagic stroke. Dr. Dong and coworkers review recent observations from application of histone deacetylase inhibitors to combat the effects of ischemic and hemorrhagic stroke. Dr. Thiex outlines the identification of desmoteplase, a highly fibrin-selective plasminogen activator with high fibrinolytic potential, as a novel candidate in fibrinolytic therapy for intracerebral hemorrhage. The wide variety of approaches to the treatment of stroke also includes adult stem cell transplantation. Dr. Zhou presents a ground-breaking therapeutic strategy for stroke using mesenchymal stem cells, which have the potential to differentiate into both neural stem cells and neurons. Finally, Dr. Giffard and coworkers provide a thorough overview of the current literature on astrocytes as targets for neuroprotection in stroke; they outline the essential functions of astrocytes (both protective of and threatening to neurons) and discuss how manipulating these functions provides a novel and important strategy to enhance neuronal survival and improve outcomes following stroke. We hope that this hot-topic issue on stroke will be a highly useful resource for basic researchers, medicinal chemists, clinicians, and students around the world.

Stroke is the third leading cause of mortality and disability in the United States. Ischemic stroke constitutes 85% of all stroke cases. However, no effective treatment has been found to prevent damage to the brain in such cases except tissue plasminogen activator with narrow therapeutic window, and there is an unmet need to develop therapeutics for neuroprotection from ischemic stroke. Studies have shown that mechanisms including apoptosis, necrosis, inflammation, immune modulation, and oxidative stress and mediators such as excitatory amino acids, nitric oxide, inflammatory mediators, neurotransmitters, reactive oxygen species, and withdrawal of trophic factors may lead to the development of the ischemic cascade. Hence, it is essential to develop neuroprotective agents targeting either the mechanisms or the mediators leading to development of ischemic stroke. This review focuses on central nervous system agents targeting these biochemical pathways and mediators of ischemic stroke, mainly those that counteract apoptosis, inflammation, and oxidation, and well as glutamate inhibitors which have been shown to provide neuroprotection in experimental animals. All these agents have been shown to improve neurological outcome after ischemic insult in experimental animals in vivo, organotypic brain slice/acute slice ex vivo, and cell cultures in vitro and may therefore aid in preventing long-term morbidity and mortality associated with ischemic stroke.

Due to a lack of efficient treatments, searching for novel therapies against acute ischemic stroke represents one of the main fields in neuropharmacology. In this review we summarize and discuss the role of mitochondrial participation in ischemia-induced neuronal death. Mitochondria are regarded as the main link between cellular stress signals and the execution of programmed death of nerve cells. Since it was described that the release of mitochondrial proteins such as cytochrome c, apoptosis inducing factor and endonuclease G are key elements in cell death pathways, they have been the focus of cell death studies. Changes in the permeability of the mitochondrial outer membrane result in a non-reversible step in cell death processes. Cytochrome c released from mitochondria binds in the cytoplasm to Apaf-1 to initiate the formation of an apoptosome, which then binds pro-caspase-9. Active caspase-9 cleaves “executioner” caspases, which in turn proceed to cleave key substrates in the cell. Thus, the identification of new targets might enable establishment of novel strategies for therapeutic research, in this case based on the molecular mechanisms of mitochondrial pathways, to improve the development of compounds for treatment of ischemia.

Cerebral ischemia is characterized by obvious inflammatory cell aggregations, up-regulation of cytokine expression, and increased expression of intercellular adhesion molecules. Like systemic bacterial infections, cerebral injury is also associated with innate immunity, a specific immunologic response that utilizes Toll-like receptors (TLRs). The involvement of TLRs in cerebral ischemia is now being confirmed using animal models. Recent reports reveal that mice that lack TLR2 and TLR4 show improved stroke outcomes and that TLR2 and 4 may contribute to neuronal injury that occurs after cerebral ischemia. In this review, we have summarized these recent reports concerning the association of TLRs with cerebral ischemia.

Selective neuronal cell death is one of the major causes of neuronal damage following stroke, and cerebral cells naturally mobilize diverse survival signaling pathways to protect against ischemia. Importantly, therapeutic strategies designed to improve endogenous anti-apoptotic signaling appear to hold great promise in stroke treatment. While a variety of complex mechanisms have been implicated in the pathogenesis of stroke, the overall mechanisms governing the balance between cell survival and death are not well-defined. Ras family small GTPases are activated following ischemic insults, and in turn, serve as intrinsic switches to regulate neuronal survival and regeneration. Their ability to integrate diverse intracellular signal transduction pathways makes them critical regulators and potential therapeutic targets for neuronal recovery after stroke. This article highlights the contribution of Ras family GTPases to neuroprotective signaling cascades, including mitogen-activated protein kinase (MAPK) family protein kinase- and AKT/PKB-dependent signaling pathways as well as the regulation of cAMP response element binding (CREB), Forkhead box O (FoxO) and hypoxiainducible factor 1(HIF1) transcription factors, in stroke.

Histone deacetylases (HDACs) play a key role in the homeostasis of histone acetylation and gene transcription. Histone hypoacetylation and transcriptional dysfunction have been identified in a large number of neurological diseases, including ischemic and hemorrhagic stroke. HDAC inhibitors (HDACi) have emerged as a promising therapeutic intervention in neurodegenerative disorders. Here we review and discuss recent observations in the application of the HDACi to combat the effects of stroke in animal and cell culture models. These agents raise histone acetylation levels, adjust the transcription of associated genes, and exert neuroprotective benefits against stroke. Clinical randomized trials should be performed to further investigate the benefits of HDACi for stroke patients.

Intracerebral hemorrhage (ICH) is associated with a high mortality and severe disability. Whereas a classical open craniotomy for hematoma removal may further traumatize brain tissue, minimally invasive surgery combines benefits of surgical clot removal with limited tissue damage and shorter surgery duration. Evacuation is often hampered by clot retraction, thus, advocating clot liquefaction to facilitate complete evacuation. The use of urokinase or recombinant tissue plasminogen activator (rtPA) alone and in combination with neuroprotective drugs in experimental studies and clinical trials is reviewed with respect to efficacy in hematoma reduction and effects on secondary brain injury. Whereas rtPA promotes delayed edema formation and inflammation after local fibrinolysis, desmoteplase (DSPA), a highly fibrin-selective plasminogen activator derived from vampire bat saliva, combines high fibrinolytic potential with lack of excitotoxicity, thus representing a novel, promising candidate for fibrinolytic therapy of ICH.

Human adult skeletal stem cells, a.k.a. mesenchymal stem cells or marrow stromal cells (MSCs), have been identified as precursors of several different mesenchymal cellular lineages, including osteoblasts, chondrocytes, myoblasts, adipocytes, and fibroblasts, as well as non-mesenchymal lineages including neurons and glial cells. Adult stem cell transplantation is a promising strategy for the treatment of stroke. MSCs are also used as a platform for gene therapies and therapeutic agents. In this review, we discuss recent progress of human skeletal stem cell biology, in vitro differentiation of MSCs into neural stem cells and neurons, MSC therapy for stroke, MSC aging and the challenge of autologous cell therapy for stroke in elderly patients.

In the past two decades, over 1000 clinical trials have failed to demonstrate a benefit in treating stroke, with the exception of thrombolytics. Although many targets have been pursued, including antioxidants, calcium channel blockers, glutamate receptor blockers, and neurotrophic factors, often the focus has been on neuronal mechanisms of injury. Broader attention to loss and dysfunction of non-neuronal cell types is now required to increase the chance of success. Of the several glial cell types, this review will focus on astrocytes. Astrocytes are the most abundant cell type in the higher mammalian nervous system, and they play key roles in normal CNS physiology and in central nervous system injury and pathology. In the setting of ischemia astrocytes perform multiple functions, some beneficial and some potentially detrimental, making them excellent candidates as therapeutic targets to improve outcome following stroke and in other central nervous system injuries. The older neurocentric view of the central nervous system has changed radically with the growing understanding of the many essential functions of astrocytes. These include K+ buffering, glutamate clearance, brain antioxidant defense, close metabolic coupling with neurons, and modulation of neuronal excitability. In this review, we will focus on those functions of astrocytes that can both protect and endanger neurons, and discuss how manipulating these functions provides a novel and important strategy to enhance neuronal survival and improve outcome following cerebral ischemia.